Inhibition of effects of endogenously synthesized histamine disturbs in vitro human dendritic cell differentiation

Histamine, a principal mediator in various physiological and pathological c ell functions is synthesized from L-histidine exclusively by histidine deca rboxylase, an enzyme, which is expressed in many tissues of mammalian organ ism. Histamine plays a role in various cellular functions, including cell d ifferentiation. The aim of this study was to determine the presence and to characterize the role of the endogenously produced histamine during in vitr o dendritic cell (DC) differentiation induced by interleukin-4 (IL-4) and g ranulocyte-monocyte colony stimulating factor (GM-CSF). The changes in intr acellular histamine content, biosynthesis and gene expression of histidine decarboxylase were investigated during this process. One also studied how h istamine receptor antagonists and a histamine synthesis blocker influence t he expression of differentiation antigens on the DC during in vitro maturat ion. During in vitro differentiation parallel culture incubations were perf ormed by adding H1 receptor antagonist triprolidine, H2 receptor antagonist tiotidine, the tamoxifene derivate DPPE which blocks the intracellular bin ding of histamine, and an irreversible blocker of histidine decarboxylase, alpha -fluoromethyl histamine (alpha -FMH). The results show simultaneous i ncrease in both histidine decarboxylase level and histamine content during differentiation of elutriated monocytes toward DC. Both blockade of de novo histamine production (by a-FMH) and inhibition of histamine binding (by H1 and H2 receptor antagonists, triprolidine and tiotidine, respectively) mar kedly decreased CD40 expression and that of CD45 from the 3rd day of treatm ent. DPPE by disturbing intracellular interaction of histamine with cytochr ome P-450 moieties was able to decrease the expression of CD45, CD86, HLA-D R, CD33, CD40 and CD11c. Based on the data it is suggested that endogenous histamine is actively synthesized during cytokine-induced in vitro DC diffe rentiation. The functional relevance and autocrine and paracrine action of endogenously produced histamine is supported by the data showing that inhib ition of histamine synthesis by HDC, blocking of histamine binding by both 'extracellular' histamine receptors (by specific antagonists, triproridine and tiotidine) and 'intracellular' antagonists (DPPE) disturb the different iation of DC. This conclusion is supported by the fact, that by the inhibit ion of histamine acting in an autocrine/paracrine way, the expression patte rn of differentiation markers on DC is markedly changed. (C) 2001 Elsevier Science B.V. All rights reserved.